Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

• DOI: 10.1007/s00018-022-04137-0
• Publication Date: 2022-02-19T13:04:43Z
• Authors: Qingfeng Wu; Shiren Sun; Lei Wei; Minna Liu; Hao Liu; Ting Liu; Ying Zhou; Qing Jia; Di Wang; Zhen Yang; Menglu Duan; Xiaoxia Yang; Peisong Gao; Xiaoxuan Ning
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Galectin 3; Twist-Related Protein 1; Macrophage Activation; Fibrosis; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals; Humans; Original Article; Kidney Diseases; Signal Transduction; Ureteral Obstruction

AbstractRenal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.